BMP2 and BMP7 play antagonistic roles in feather induction

Feathers, like hairs, first appear as primordia consisting of an epidermal placode associated with a dermal condensation that is necessary for the continuation of their differentiation. Previously, the BMPs have been proposed to inhibit skin appendage formation. We show that the function of specific BMPs during feather development is more complex. BMP2 and BMP7, which are expressed in both the epidermis and the dermis, are involved in an antagonistic fashion in regulating the formation of dermal condensations, and thus are both necessary for subsequent feather morphogenesis. BMP7 is expressed earlier and functions as a chemoattractant that recruits cells into the condensation, whereas BMP2 is expressed later, and leads to an arrest of cell migration, likely via its modulation of the EIIIA fibronectin domain and α4 integrin expression. Based on the observed cell proliferation, chemotaxis and the timing of BMP2 and BMP7 expression, we propose a mathematical model, a reaction-diffusion system, which not only simulates feather patterning, but which also can account for the negative effects of excess BMP2 or BMP7 on feather formation.

[1]  D. Dhouailly,et al.  Differential regulation of the chick dorsal thoracic dermal progenitors from the medial dermomyotome. , 2002, Development.

[2]  P K Maini,et al.  Stripe formation in juvenile Pomacanthus explained by a generalized turing mechanism with chemotaxis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Miyazono.  Signal transduction by bone morphogenetic protein receptors: functional roles of Smad proteins. , 1999, Bone.

[4]  P. Goetinck,et al.  FGF‐2 signaling is sufficient to induce dermal condensations during feather development , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[5]  R. Kramer,et al.  Modulation of satellite cell adhesion and motility following BMP2-induced differentiation to osteoblast lineage. , 2007, Biochemical and biophysical research communications.

[6]  L. Niswander,et al.  Requirement for BMP Signaling in Interdigital Apoptosis and Scale Formation , 1996, Science.

[7]  B. Morgan,et al.  BMPs mediate lateral inhibition at successive stages in feather tract development. , 1998, Development.

[8]  Viktor Hamburger,et al.  A series of normal stages in the development of the chick embryo , 1992, Journal of morphology.

[9]  M. Bronner‐Fraser,et al.  Id4 expression and its relationship to other Id genes during avian embryonic development , 2001, Mechanisms of Development.

[10]  V. Botchkarev.  Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. , 2003, The Journal of investigative dermatology.

[11]  D. Hartmann,et al.  Immunofluorescent localization of collagen types I and III, and of fibronectin during feather morphogenesis in the chick embryo. , 1982, Developmental biology.

[12]  H. Meinhardt,et al.  A theory of biological pattern formation , 1972, Kybernetik.

[13]  M. Charvéron,et al.  Dermal condensation formation in the chick embryo: Requirement for integrin engagement and subsequent stabilization by a possible Notch/integrin interaction , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[14]  R. Benezra,et al.  Inhibition of myeloid differentiation by the helix-loop-helix protein Id. , 1992, Science.

[15]  C. Abate-Shen,et al.  Dlx genes integrate positive and negative signals during feather bud development. , 2004, Developmental biology.

[16]  C. Chuong,et al.  FGF induces new feather buds from developing avian skin. , 1996, The Journal of investigative dermatology.

[17]  C. Chuong,et al.  Asymmetric expression of Notch/Delta/Serrate is associated with the anterior-posterior axis of feather buds. , 1997, Developmental biology.

[18]  N. Ueno,et al.  Efficient expression of a heterodimer of bone morphogenetic protein subunits using a baculovirus expression system. , 1995, Biochemical and biophysical research communications.

[19]  K. Miyazono,et al.  Id: A Target of BMP Signaling , 2002, Science's STKE.

[20]  B. Vandenbunder,et al.  The relationship between cell proliferation and the transcription of the nuclear oncogenes c-myc, c-myb and c-ets-1 during feather morphogenesis in the chick embryo. , 1991, Development.

[21]  L Wolpert,et al.  Local inhibitory action of BMPs and their relationships with activators in feather formation: implications for periodic patterning. , 1998, Developmental biology.

[22]  K. Sekiguchi,et al.  Modulation of Cell-adhesive Activity of Fibronectin by the Alternatively Spliced EDA Segment , 1997, The Journal of cell biology.

[23]  K. Patel,et al.  The role of long range, local and direct signalling molecules during chick feather bud development involving the BMPs, Follistatin and the Eph receptor tyrosine kinase Eph-A4 , 1999, Mechanisms of Development.

[24]  J. Nordlund.  Morphogenesis of the Skin , 1977, The Yale Journal of Biology and Medicine.

[25]  D. Lauffenburger.  Cell motility. Making connections count. , 1996, Nature.

[26]  C. Chuong,et al.  Early events during avian skin appendage regeneration: dependence on epithelial-mesenchymal interaction and order of molecular reappearance. , 1996, The Journal of investigative dermatology.

[27]  N. K. Wessells,et al.  Morphology and proliferation during early feather development. , 1965, Developmental biology.

[28]  P. Goetinck,et al.  Fibroblast growth factor 2 can replace ectodermal signaling for feather development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  D G Wilkinson,et al.  Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. , 1993, Methods in enzymology.

[30]  J. Wozney,et al.  Bone morphogenetic protein 2 transiently enhances expression of a gene, Id (inhibitor of differentiation), encoding a helix-loop-helix molecule in osteoblast-like cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  C. Clevenger.  Signal transduction. , 2003, Breast disease.

[32]  B. Robert,et al.  msh/Msx gene family in neural development. , 2005, Trends in genetics : TIG.

[33]  K. Miyazono,et al.  BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. , 2005, Cytokine & growth factor reviews.

[34]  W. Sebald,et al.  The interaction of BMP-7 and ActRII implicates a new mode of receptor assembly. , 2003, Trends in biochemical sciences.

[35]  M. Harris,et al.  Bmp7 mediates early signaling events during induction of chick epidermal organs , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  J. Viallet,et al.  Signaling dynamics of feather tract formation from the chick somatopleure , 2004, Development.

[37]  C. Chuong.  The making of a feather: Homeoproteins, retinoids and adhesion molecules , 1993, BioEssays : news and reviews in molecular, cellular and developmental biology.

[38]  E. Taylor,et al.  Cell Motility , 1986, Journal of Cell Science.

[39]  B. Morgan,et al.  The ectodysplasin pathway in feather tract development , 2005, Development.

[40]  O. Pourquié,et al.  Chick Delta-1 gene expression and the formation of the feather primordia , 1998, Mechanisms of Development.

[41]  J. Fallon,et al.  The spatial pattern and temporal sequence in which feather germs arise in the white Leghorn chick embryo. , 1985, Developmental biology.

[42]  B. Morgan,et al.  beta-catenin signaling can initiate feather bud development. , 1999, Development.

[43]  A. Nordheim,et al.  Id Genes Are Direct Targets of Bone Morphogenetic Protein Induction in Embryonic Stem Cells* , 1999, The Journal of Biological Chemistry.

[44]  P. Maini,et al.  Sequential pattern formation in a model for skin morphogenesis. , 1992, IMA journal of mathematics applied in medicine and biology.

[45]  C. Chuong,et al.  Mechanism of skin morphogenesis. I. Analyses with antibodies to adhesion molecules tenascin, N-CAM, and integrin. , 1992, Developmental biology.

[46]  A. M. Turing,et al.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[47]  C. Chuong,et al.  Self-organization of periodic patterns by dissociated feather mesenchymal cells and the regulation of size, number and spacing of primordia. , 1999, Development.

[48]  H. Yoshikawa,et al.  Bone morphogenetic protein-2 promotes the haptotactic migration of murine osteoblastic and osteosarcoma cells by enhancing incorporation of integrin beta1 into lipid rafts. , 2006, Experimental cell research.

[49]  J. Molkentin,et al.  MEKK1 Transduces Activin Signals in Keratinocytes To Induce Actin Stress Fiber Formation and Migration , 2005, Molecular and Cellular Biology.

[50]  R. Hynes,et al.  Alternative splicing of chicken fibronectin in embryos and in normal and transformed cells , 1987, Molecular and cellular biology.

[51]  Douglas A. Lauffenburger,et al.  Making connections count , 1996, Nature.

[52]  M. Nicola,et al.  Analysis of Msx1; Msx2 double mutants reveals multiple roles for Msx genes in limb development , 2005, Development.

[53]  C. Chuong,et al.  Homeobox genes Msx-1 and Msx-2 are associated with induction and growth of skin appendages. , 1995, The Journal of investigative dermatology.

[54]  B. Bardot,et al.  Drm/Gremlin, a BMP antagonist, defines the interbud region during feather development. , 2004, The International journal of developmental biology.

[55]  K. Sekiguchi,et al.  Alternatively Spliced EDA Segment Regulates Fibronectin-dependent Cell Cycle Progression and Mitogenic Signal Transduction* , 1999, The Journal of Biological Chemistry.

[56]  A. Bishop,et al.  Embryonic stem cells , 2004, Cell proliferation.

[57]  Pascal Schneider,et al.  Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression , 2007, Development.

[58]  D. Dhouailly,et al.  Dorsal dermis development depends on a signal from the dorsal neural tube, which can be substituted by Wnt-1 , 2001, Mechanisms of Development.

[59]  J. Cassiman,et al.  Localization of alpha 4m integrin at sites of mesenchyme condensation during embryonic mouse development. , 1995, Differentiation; research in biological diversity.

[60]  Hyeong-Cheol Yang,et al.  Chemotactic migration of human mesenchymal stem cells and MC3T3-E1 osteoblast-like cells induced by COS-7 cell line expressing rhBMP-7. , 2006, Tissue engineering.

[61]  Wei-Min Shen,et al.  Integument pattern formation involves genetic and epigenetic controls: feather arrays simulated by digital hormone models. , 2004, The International journal of developmental biology.